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Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.

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Molecular Cell Biology. 4th edition.

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Section 18.4Muscle: A Specialized Contractile Machine

Muscle cells have evolved to carry out one highly specialized function — contraction. Muscle contractions must occur quickly and repetitively, and they must occur through long distances and with enough force to move large loads. In muscle, actin and myosin associate into a complex, called actomyosin, which is organized into a highly ordered structure having the ability to do work very efficiently.

Like any mechanical engine, muscles can be characterized by their power output, the rate at which they can work. Muscle power depends on several parameters: velocity of contraction, ability to contract repetitively, and force of contraction. Compared with that of other cellular systems, the power output of muscle is approximately equal to that of a flagellum but is 330,000-fold higher than the power output of the mitotic spindle, the microtubule machinery that separates chromosomes. Perhaps more instructive is to compare the power output of muscle with that of mechanical engines. When corrected for weight differences, a racing car engine and an aircraft engine are only tenfold to fortyfold more powerful than a muscle. A passenger car engine is only 1½ times more powerful than muscle. In muscle, nature has obviously designed a very efficient and powerful engine.

In this section, we build on our discussion of myosin II as a motor protein by describing how myosin and actin are organized in muscle and how the motor properties of myosin are exploited to contract a muscle. Although we concentrate on the structure and function of skeletal muscle, the best-understood type of muscle, we also describe important details of smooth muscle, whose structure and activity are very similar to actin-myosin structures in nonmuscle cells. Thus when we later examine these structures in nonmuscle cells, we will understand how they generate movement but why they are less efficient than the muscle actomyosin system.

Some Muscles Contract, Others Generate Tension

Vertebrates and many invertebrates have two classes of muscle — skeletal and smooth — which differ in function. (A third class of muscle found in vertebrates, cardiac [heart] muscle, is not discussed here.) Skeletal muscles connect the bones in the arms, legs, and spine and are used in complex coordinated activities, such as walking or positioning of the head; they generate rapid movements by contracting quickly. In this type of contraction, termed isotonic contraction, the muscle shortens as force is generated. Another major function of skeletal muscle is to hold objects immobile. In the clenching of fists or tensing of muscles, for example, pairs of contracting muscles work to oppose each other and thus cancel out any movements. In such isometric contraction, the overall length of a muscle remains constant but its tension increases. Smooth muscles surround internal organs such as the large and small intestines, the uterus, and large blood vessels. The contraction and relaxation of smooth muscles controls the diameter of blood vessels and also propels food along the gastrointestinal tract. Compared with skeletal muscles, smooth muscle cells contract and relax slowly, and they can create and maintain tension for long periods of time.

Skeletal Muscles Contain a Regular Array of Actin and Myosin

A skeletal muscle comprises a bundle of muscle cells, or myofibers (Figure 18-26a). A typical muscle cell is cylindrical, large (1 – 40 mm in length and 10 – 50 μm in width), and multinucleated (containing as many as 100 nuclei). A myofiber is packed with myofibrils, bundles of filaments that extend the length of the cell. Myofibrils are further subdivided into alternating light and dark bands, which are aligned along the length of the muscle cell, giving the myofiber a striated appearance in the light microscope. Closer examination reveals that the dark bands, called A bands, are bisected by a dark region, the H zone, while the light bands, called I bands, are bisected by a different dark line, the Z disk. (The latter is also called the Z line because it appears as a line when seen in profile in electron micrographs.) The segment from one Z disk to the next, consisting of two halves of an I band and an A band, is termed a sarcomere.

Figure 18-26. General structure of skeletal and smooth muscle.

Figure 18-26

General structure of skeletal and smooth muscle. (a) Skeletal muscle tissue is composed of bundles of multinucleated muscle cells, or myofibers. Each muscle cell is packed with bundles of (more...)

A chain of sarcomeres, each about 2 μm long in resting muscle, constitutes a myofibril. The sarcomere is both the structural and the functional unit of skeletal muscle. During contraction, the sarcomeres are shortened to about 70 percent of their uncontracted, resting length. Electron microscopy and biochemical analysis have shown that each sarcomere contains two types of filaments: thick filaments, composed of myosin II, and thin filaments, containing actin (Figure 18-27). Near the center of the sarcomere, thin filaments overlap with the thick filaments in the AI zone.

Figure 18-27. Structure of the sarcomere.

Figure 18-27

Structure of the sarcomere. (a) Electron micrograph of mouse striated muscle in longitudinal section, showing one sarcomere. On either side of the Z disks are the lightly stained I bands, (more...)

Thick Filaments

Salt extraction of skeletal muscle dissolves the thick filaments, causing loss of the A bands, but the thin filaments and I bands remain. Biochemical analysis shows that myosin but not actin is extracted, and dialysis of the extracted myosin into low-salt solutions reconstitutes thick filaments. Thus myosin is the primary structural component of the thick filaments. Because the myosin molecules composing a thick filament are oriented with their heads lying at the distal tips of the filament and their tails at the center, the filament is bipolar (see Figure 18-27b).

Thin Filaments

The I band is a bundle of thin filaments. All the filaments in an I band are the same length, but can vary among different muscles. Biochemical studies show that a thin filament is basically an actin filament plus two additional proteins, tropomyosin and troponin, that are involved in regulating actomyosin interactions. Evidence that actin is the main component of thin filaments is drawn from findings in three experiments. First, thin filaments appear identical with actin filaments reconstituted from purified G-actin monomers. Second, the thin filaments can be decorated with myosin S1 or HMM. Third, thin filaments but not thick filaments can be removed with the actin-severing protein gelsolin.

In electron micrographs, one end of a thin filament is associated with the Z disk, while the other end is near the center of the sarcomere (see Figure 18-27a, b). Myosin decoration experiments show that all thin filaments have the same polarity with respect to the Z disk: The barbed or (+) end of the filament is always closest to the Z disk. The heads of the myosin molecules protrude from the thick filaments, in the AI zone, forming cross-bridges with adjacent actin thin filaments (see Figure 18-27c).

The ends of a thin filament are associated with two actin-capping proteins, CapZ and tropomodulin (Figure 18-28). CapZ is present in the Z disk of skeletal muscle, where it helps prevent actin filaments from depolymerizing at their (+) end. CapZ probably also cross-links the (+) ends of actin filaments to other Z-disk proteins. At the opposite end of the thin filament lies tropomodulin, which protects the (−) end from depolymerization, as it does in the erythrocyte cytoskeleton. Capping at both ends causes thin filaments to be very stable.

Figure 18-28. Schematic diagram showing location of capping proteins that stabilize the ends of actin thin filaments.

Figure 18-28

Schematic diagram showing location of capping proteins that stabilize the ends of actin thin filaments. CapZ (green) caps the (+), or barbed, ends of filaments at the Z disk, and (more...)

The Z Disk

The Z disk is a lattice of fibers whose major function is to anchor the (+) ends of actin filaments. How the filaments are attached is not certain, but scientists believe that the actin-capping protein CapZ and the actin cross-linking protein α-actinin play a role. A major component of isolated Z disks, α-actinin probably cross-links thin filaments in the I band, organizing them into a bundle of filaments.

Smooth Muscles Contain Loosely Organized Thick and Thin Filaments

A smooth muscle is composed of elongated spindle-shaped cells, each with a single nucleus. Although smooth muscle cells are packed with thick and thin filaments, these filaments are not organized into well-ordered sarcomeres and myofibrils, as they are in skeletal muscle; for this reason, smooth muscle is not striated. Instead the filaments in smooth muscle are gathered into loose bundles, which are attached to dense bodies in the cytosol (see Figure 18-26b). Dense bodies apparently serve the same function as Z disks in skeletal muscle. The other end of the thin filaments in many smooth muscle cells is connected to attachment plaques, which are similar to dense bodies but are located at the plasma membrane of a muscle cell. Like a Z disk, an attachment plaque is rich in the actin-binding protein α-actinin; it also contains a second protein, vinculin (MW 130,000), not found in Z disks. Vinculin, which binds tightly to α-actinin in cell-free experiments, binds directly to an integral membrane protein in the plaque and to α-actinin, thereby attaching actin filaments to membrane adhesion sites.

Thick and Thin Filaments Slide Past One Another during Contraction

Previously, we examined the in vitro movement of myosin along actin filaments. These in vitro motility studies, combined with microscopy studies in the 1950s that showed thick and thin filaments did not change in length while the sarcomere shortened, led to a simple model of skeletal muscle contraction, called the sliding-filament model (Figure 18-29).

Figure 18-29. The sliding-filament model of contraction in striated muscle.

Figure 18-29

The sliding-filament model of contraction in striated muscle. The arrangement of thick myosin and thin actin filaments in the relaxed state is shown in the top diagram. In the presence of (more...)

The central tenet of this model is that ATP-dependent interactions between thick filaments (myosin) and thin filaments (actin) generate a force that causes thin filaments to slide past thick filaments. The force is generated by the myosin heads of thick filaments, which form cross-bridges to actin thin filaments in the AI zone, where the two filament systems overlap. Subsequent conformational changes in these cross-bridges cause the myosin heads to walk along an actin filament, as discussed earlier. The sliding-filament model predicted that the force of contraction should be proportional to the overlap between the two filament systems.

To understand how a muscle contracts, consider the interactions between one myosin head (among the hundreds in a thick filament) and a thin filament as diagrammed in Figure 18-25. During these steps, also called the cross-bridge cycle, a myosin head has moved two subunits closer to the Z disk or the (+) end of the filament. Because the thick filament is bipolar, the action of the myosin heads at opposite ends of the thick filament draws the thin filaments toward the center of the thick filament and therefore toward the center of the sarcomere (see Figure 18-29). This movement shortens the sarcomere until the ends of the thick filaments abut the Z disk or the (−) ends of the thin filaments overlap at the center of the A band. Contraction of an intact muscle results from the activity of hundreds of myosin heads on a single thick filament, amplified by the hundreds of thick filaments in a sarcomere and thousands of sarcomeres in a muscle fiber.

The sliding-filament model, first proposed about 50 years ago, has been supported by more recent experimental results. In particular, the three-dimensional structure of the myosin head determined by x-ray crystallography and the force and step size measured during in vitro movement of single myosin molecules are compatible with the model (see Figures 18-22 and 18-23).

Titin and Nebulin Filaments Organize the Sarcomere

Muscle is elastic like a rubber band. Resting muscle can be stretched until the thick and thin filaments no longer overlap, developing a resisting force, or passive tension, which can be greater than the force normally developed by contracting muscle. If the stretching forces are removed, the muscle quickly resumes its normal resting length, and the regular arrangement of thick and thin filaments is restored. The source of this inherent elasticity was an enigma until scientists discovered a distinctive set of extremely long proteins, which organize the thick and thin filaments in their three-dimensional arrays and give muscle much of its elastic properties.

One component of this third filament system is the gigantic fibrous protein titin (also called connectin), which connects the ends of myosin thick filaments to Z disks and extends along the thick filament to the H zone (Figure 18-30). Titin appears to function like an elastic band, keeping the myosin filaments centered in the sarcomere when muscle contracts or is stretched. As its name suggests, titin is huge (≈2,700,000 MW; that is, over 25,000 amino acids); the protein is about 1 μm long, a length that spans half of a sarcomere. Most of its length is due to multiple repeats of immunoglobulin and fibronectin domains.

Figure 18-30. The titin-nebulin filament system stabilizes the alignment of thick and thin filaments in skeletal muscle.

Figure 18-30

The titin-nebulin filament system stabilizes the alignment of thick and thin filaments in skeletal muscle. (a) A titin filament attaches at one end to the Z disk and spans the distance to (more...)

As noted earlier, salt treatment of muscle removes the thick filaments. Thin filaments, however, retain their regular organization in salt-treated muscle, suggesting that the lattice of thin filaments is maintained by a salt-resistant structure. Another large protein, called nebulin (≈700,000 MW), is thought to perform this role. Nebulin forms long nonelastic filaments, consisting of a repeating actin-binding domain, that extend from each side of the Z disk and along the thin filaments (see Figure 18-30a). Each nebulin filament is as long as its adjacent actin filament; thus nebulin also may act as a molecular ruler by regulating the number of actin monomers that polymerize into each thin filament during the formation of mature muscle fibers. Treatment of muscle with the actin-severing protein gelsolin removes the thin filaments; without supporting thin filaments, nebulin filaments condense at the Z disk, leaving the titin filaments and myosin thick filaments (Figure 18-30b).

A Rise in Cytosolic Ca2+ Triggers Muscle Contraction

Like many cellular processes, muscle contraction is initiated by an increase in the cytosolic Ca2+ concentration. As described in Chapter 15, the Ca2+ concentration of the cytosol is normally kept low, below 0.1 μM. Nonmuscle cells maintain this low concentration by Ca2+ ATPases in the plasma membrane, which pump calcium out of the cell. In contrast, skeletal muscle cells maintain a low cytosolic Ca2+ level primarily by a unique Ca2+ ATPase that continually pumps Ca2+ ions from the cytosol into the sarcoplasmic reticulum (SR), a network of tubules in the muscle-cell cytosol. This activity establishes a reservoir of calcium in the SR.

As discussed in later chapters, when a nerve impulse reaches a skeletal muscle cell, it causes a change in the electric potential across the plasma membrane. Skeletal muscle cells can rapidly convert this electrical signal (called depolarization) into a rise in cytosolic Ca2+ (chemical signal), which then initiates contraction by a mechanism described later. The major anatomic features of this signaling pathway are invaginations of the plasma membrane, called T (transverse) tubules, that terminate next to the SR, forming structures called triads (Figure 18-31a). This system brings the membrane depolarization signal into the cytosol at a triad, where it stimulates the SR to release stored calcium into the cytosol through Ca2+ channels in the SR membrane (Figure 18-31b). Because of the close apposition of T tubules and SR membranes, depolarization of the plasma membrane induces an increase in cytosolic Ca2+ and contraction within milliseconds. Conversely, a muscle stops contracting when the channels close and Ca2+ is pumped back into the SR.

Figure 18-31. The sarcoplasmic reticulum (SR) regulates the cytosolic Ca2+ level in skeletal muscle.

Figure 18-31

The sarcoplasmic reticulum (SR) regulates the cytosolic Ca2+ level in skeletal muscle. (a) Three-dimensional drawing of a portion of a muscle cell (myofiber) composed of six myofibrils. (more...)

In smooth muscle cells, the SR membrane network is poorly developed and sparse, and much of the increase in cytosolic Ca2+ necessary for muscle contraction enters the cell via the plasma-membrane Ca2+ channel. As a result, changes in the cytosolic Ca2+ level occur much more slowly in smooth muscle than in skeletal muscle — on the order of seconds to minutes — thereby allowing the slow, steady response in contractile tension that is required by vertebrate smooth muscle.

Actin-Binding Proteins Regulate Contraction in Both Skeletal and Smooth Muscle

With the exception of cardiac muscle cells, which must contract rhythmically throughout the lifetime of the animal, all other muscles exhibit periods of activity followed by inactivity. In Chapters 20 and 21, we discuss in detail how cells recognize various external signals — electrical, hormonal, and chemical — that act to excite various intercellular responses, including the rise in cytosolic Ca2+ that initiates muscle contraction. So long as the Ca2+ concentration is sufficiently high and ATP is present in a muscle, the myosin-actin cross bridges will cycle continuously (see Figure 18-25), causing filament movement and contraction. Here we examine how actin-binding proteins mediate the Ca2+ signal to regulate skeletal and smooth muscle.

Role of Tropomyosin and Troponin in Skeletal Muscle Contraction

In skeletal muscle, contraction is regulated by four accessory proteins on the actin thin filaments: tropomyosin and troponins C, I, and T. The cytosolic Ca2+ concentration influences the position of these proteins on the thin filaments, which in turn controls myosin-actin interactions.

Tropomyosin (TM) is a ropelike molecule, about 40 nm in length; TM molecules are strung together head to tail, forming a continuous chain along each actin thin filament (Figure 18-32a). Each TM molecule has seven actin-binding sites and binds to seven actin monomers in a thin filament. Associated with tropomyosin is troponin (TN), a complex of the three subunits, TN-T, TN-I, and TN-C. TN-C is the calcium-binding subunit of troponin. Similar in sequence to calmodulin and the myosin light chains, TN-C controls the position of TM on the surface of an actin filament through the TN-I and TN-T subunits.

Figure 18-32. Effect of Ca2+ ions on tropomyosin binding to actin filaments.

Figure 18-32

Effect of Ca2+ ions on tropomyosin binding to actin filaments. (a) Model of the tropomyosin-troponin (TM-TN) regulatory complex on a thin filament. TN, a clublike complex of TN-C, (more...)

Scientists currently think that, under the control of Ca2+ and TN, TM can occupy two positions on a thin filament — an “off” state and an “on” state. In the absence of Ca2+ (the off state), myosin can bind to a thin filament, but the TM-TN complex prevents myosin from sliding along the thin filament. Binding of Ca2+ ions to TN-C triggers a slight movement of TM toward the center of the actin filament (the on state), which exposes the myosin-binding sites on actin (Figure 18-32b). Thus Ca2+ concentrations > 10−6 M relieve the inhibition exerted by the TM-TN complex and contraction occurs. The Ca2+-dependent cycling between on and off states in skeletal muscle is summarized in Figure 18-33a.

Figure 18-33. Ca2+-dependent mechanisms for regulating contraction in skeletal and smooth muscle.

Figure 18-33

Ca2+-dependent mechanisms for regulating contraction in skeletal and smooth muscle. (a) Regulation of skeletal muscle contraction by Ca2+ binding to TN. Note that the TM-TN (more...)

Role of Caldesmon in Smooth Muscle Contraction

Several properties of smooth muscle account for its slow, steady contractile response. First, the actomyosin network is more disordered in vertebrate smooth muscle than in skeletal muscle. Second, as explained above, the cytosolic Ca2+ level rises and falls much more slowly in smooth muscle than in skeletal muscle. Finally, although smooth muscle contains tropomyosin (TM), it lacks troponin (TN), so the TM-TN system for rapidly turning skeletal muscle on and off cannot operate.

There are, in fact, several pathways that stimulate or inhibit smooth muscle contraction. One pathway, the smooth muscle equivalent of the TM-TN system, involves caldesmon, which binds to actin thin filaments at low Ca2+ concentrations (Figure 18-33b). Caldesmon (150,000 MW), an elongated protein about 75 nm in length, also interacts with the Ca2+-calmodulin complex at higher Ca2+ levels. Thus, when Ca2+ ions are in short supply, caldesmon forms a complex with TM and actin, thereby restricting the ability of myosin to bind to actin and preventing contraction. The binding of caldesmon to actin also is influenced by its phosphorylation by various kinases, including mitogen activated protein (MAP) kinase. The phosphorylated form of caldesmon does not bind well to thin filaments and is unable to inhibit myosin from binding to actin. During a prolonged contraction, MAP kinase activity is stimulated by pathways that signal through PK-C, Ras, and heterotrimeric G-proteins. As a result, MAP kinase directly stimulates smooth muscle contraction.

Myosin-Dependent Mechanisms Also Control Contraction in Some Muscles

So far we have examined control of actomyosin interactions by proteins that associate with actin filaments. However, smooth muscle and invertebrate skeletal muscle are also regulated by several mechanisms directed toward myosin rather than actin (Figure 18-34). In these muscles, Ca2+ activates myosin in two ways: by binding to the regulatory light chains of myosin or by stimulating calcium-dependent phosphorylation of those light chains. Various hormonal signals also activate or inhibit contraction of these muscles.

Figure 18-34. Three myosin-dependent mechanisms for regulating muscle contraction.

Figure 18-34

Three myosin-dependent mechanisms for regulating muscle contraction. (a) In invertebrate muscle, binding of Ca2+ to the myosin regulatory light chain (LC) activates contraction. (b) In (more...)

Calcium-Binding to the Regulatory Light Chain

The simplest example of myosin-linked regulation is found in invertebrate muscle. Typically, in mollusks such as the scallop, the interaction between myosin heads and actin filaments is inhibited at low Ca2+ concentrations by the regulatory light chain (LC), one of the two pairs of LCs in the myosin neck region (see Figures 18-20 and 18-24). When the Ca2+ concentration rises, binding of Ca2+ ions to the regulatory LC in the neck region induces a conformational change in the myosin head that allows it to bind to actin; this, in turn, permits activation of the myosin ATPase and contraction of the muscle (see Figure 18-34a).

Activation of Myosin by Calcium-Dependent Phosphorylation

Contraction of vertebrate smooth muscle is regulated primarily by a complex pathway involving phosphorylation and dephosphorylation of the myosin regulatory LC. As in mollusks, one of the two myosin LC pairs in smooth muscle inhibits actin stimulation of the myosin ATPase activity at low Ca2+ concentrations. This inhibition is relieved and the smooth muscle contracts when the regulatory LC is phosphorylated by the enzyme myosin LC kinase (see Figure 18-34b). This enzyme is activated by Ca2+; thus the Ca2+ level indirectly regulates the extent of LC phosphorylation and hence contraction. The Ca2+-dependent regulation of myosin LC kinase activity is mediated through calmodulin. Calcium first binds to calmodulin, and the Ca2+-calmodulin complex then binds to myosin LC kinase and activates it. Because this mode of regulation relies on the diffusion of Ca2+ and the action of protein kinases, muscle contraction is much slower in smooth muscle than in skeletal muscle.

The role of activated myosin LC kinase can be demonstrated by microinjecting a kinase inhibitor into smooth muscle cells. Even though the inhibitor does not block the rise in the cytosolic Ca2+ level associated with membrane depolarization, injected cells cannot contract. The effect of the inhibitor can be overcome by microinjecting a proteolytic fragment of myosin LC kinase that is active even in the absence of Ca2+-calmodulin (this treatment also does not affect Ca2+ levels).

Activation of Myosin by Rho Kinase

Unlike skeletal muscle, which is stimulated to contract solely by nerve impulses, smooth muscle is regulated by many types of molecules in addition to nervous stimuli. For example, factors such as norepinephrine, angiotensin, endothelin, and histamine as well as growth factors and hormones can modulate or induce contraction of smooth muscle by triggering various signal-transduction pathways that also affect nonmuscle cells (Chapter 20). These pathways regulate smooth muscle by modulating cytosolic Ca2+ levels and the activities of various enzymes, including myosin LC kinase and myosin phosphatase. As described above, for example, low levels of calcium stimulate myosin activity by activating myosin LC kinase. However, high levels of calcium inactivate the kinase through the action of calmodulin-dependent protein kinase II. More recent studies show how the Rho pathway stimulates myosin activity and leads to the formation of stress fibers. First, Rho kinase can phosphorylate myosin LC phosphatase and inhibit its activity. Because the phosphatase is inactivated, the level of myosin LC phosphorylation, and thus myosin activity, increases. In addition, Rho kinase directly activates myosin by phosphorylating the regulatory light chain. Thus regulation of smooth muscle contraction is complex because it is responsive to many extracellular factors in addition to intracellular Ca2+ levels.

SUMMARY

  •  A skeletal muscle cell (myofiber) consists of multiple myofibrils. In each myofibril, actin thin filaments and myosin thick filaments are organized into a linear chain of highly ordered structures, called sarcomeres (see Figure 18-27a, b). One end of the thin filaments is attached to the Z disk, the demarcation between adjacent sarcomeres. Much of the length of the thin filaments overlaps the thick filaments.
  •  Two very large proteins, titin and nebulin, hold thin and thick filaments in the regular three-dimensional array of the sarcomere (see Figure 18-30).
  •  During contraction, each sarcomere shortens by as much as 30 percent as the thin actin filaments slide past the thick filaments (see Figure 18-29). ATP-dependent interactions between myosin heads and actin and the subsequent conformational change in the heads generates the sliding force that pulls the thin filaments toward the central A zone of each sarcomere.
  •  In a smooth muscle cell, actin and myosin filaments are packed in loose bundles rather than in highly ordered myofibrils. The filaments are attached to dense bodies in the cytosol and to the plasma membrane.
  •  A rise in the cytosolic Ca2+ concentration triggers muscle contraction. Stimulation of a skeletal muscle leads to the rapid release of stored Ca2+ from the SR into the cytosol (see Figure 18-31). Following stimulation of smooth muscle, the rise in cytosolic Ca2+ and hence contraction occurs much more slowly than in skeletal muscle.
  •  Both skeletal and smooth muscles contain proteins that interact with the actin filaments to regulate contraction (see Figure 18-33). In other muscles, contraction also is regulated by binding of Ca2+ to or phosphorylation of the myosin regulatory light chains, leading to activation or inhibition of the activity of the myosin thick filaments (see Figure 18-34).

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
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